tbuckley/cabot-search huggingface dataset:
Promising antitumor activity of olverembatinib (HQP1351) in patients (pts) with tyrosine kinase inhibitor- (TKI-) resistant succinate dehydrogenase- (SDH-) deficient gastrointestinal stromal tumor (GIST).
Authors: Haibo Qiu, Zhiwei Zhou, Ye Zhou, XiangBin Wan, Kaixiong Tao, Yong Li, Xin Wu, Lihui Liu, Zi Chen, Lichuang Men, ZHIYAN LIANG, Ming Lu, Lixin Jiang, Dajun Yang, Rui-hua Xu, Yifan Zhai
Journal: Journal of Clinical Oncology (2022)

11513 Background: GIST is a rare mesenchymal tumor whose management has been transformed by approvals of TKIs. However, treatment resistance is a formidable challenge in managing locally advanced or metastatic GIST. Pts with SDH-deficient GIST are not sensitive to imatinib and other TKIs, are frequently multifocal, and typically have a multinodular architecture. Olverembatinib is a novel, potent, orally active third-generation TKI with promising activity against GIST in multiple preclinical GIST models. Methods: The aim of this phase Ib/II study was to evaluate the safety/tolerability, pharmacokinetics (PK), and efficacy (assessed per RECIST v1.1) of olverembatinib (NCT03594422) in pts with metastatic GIST whose disease was resistant or failed to respond to imatinib or other TKIs. Olverembatinib was administered orally once every other day (QOD) in 28-day repeated cycles. After 3 pts were treated at 20 mg, other pts were randomly allocated in a 1:1:1 ratio to 30, 40, and 50 mg regimens. Results: On the cutoff date of January 30, 2022, 39 pts (median age 52 [range 19-72] years) had received at least 1 dose of olverembatinib. The average (range) treatment period was 5.0 (0.2-35) months. PK analyses indicated an approximately dose-proportional increase in systemic exposure over the dose range of 20 to 50 mg. Thirty-one pts had KIT or PDGFRA mutations, 13 had stable disease for at least 2 cycles as the best response, 8 withdrew early, and 10 had progressive disease before Cycle 3. Very interestingly, 6 of 8 pts with KIT wild-type GIST were confirmed as SDH deficient: 2 pts had partial responses (PRs), 1 patient’s tumor had shrunk by 35.9% and lasted for 16 cycles, and another patient’s tumor had shrunk by 54.2% in the first evaluation. Four pts had stable disease as best response for 2, 6, 14, and 36 cycles. A total of 36 (92.3%) pts experienced treatment-emergent adverse events, most of which were mild or moderate. Ten (25.6%) pts experienced serious adverse events, of which intestinal obstruction attributed to GIST was the most reported. Common treatment-related adverse events (≥ 20%) included increased leukocyte (59.0%) and neutrophil (46.2%) counts, anemia (20.5%), constipation or asthenia (35.9% each), hyperuricemia (25.6%), hypoalbuminemia (23.1%), and elevated AST or ALT (20.5% each). Conclusions: Olverembatinib was well tolerated at doses of up to 50 mg QOD and showed antitumor activity in pts with TKI-resistant SDH-deficient GIST, with 2 PRs in 6 evaluable pts with SDH-deficient GIST and 1 with stable disease for 36 cycles. These promising findings warrant further investigation. Clinical trial information: NCT03594422.
Two oncologists, three opinions? Second opinions in oncology: Noise, bias, and disagreement.
Authors: Ernesto Gil Deza, Lourdes Gil Deza, Mariana Abal, Carlos Garcia Gerardi, Gaston Martin Reinas, Flavio A Tognelli, Marta Dragosky, Leonel Smolje, Alba Marin Ordoñez, Maximiliano Brandon, Monica Montiel, Cesar Gonzalez, María del Huerto Jaunarena, Edgardo G. J. Rivarola, Eduardo L. Morgenfeld, Daniela Gercovich
Journal: Journal of Clinical Oncology (2022)

e23009 Background: Systematic reviews show that second opinion consultations in Oncology are frequent (1 – 35%) and differ from initial recommendations by up to 50% (BMJ Open 2021;11:e044033). This study evaluates the variability of second opinions of Oncology Fellows in a Virtual Observational Standard Clinical Examination (V-OSCE 2021) (J Clin Oncol 39, 2021, suppl 15; abstr 11005). Methods: One of the stations of the V-OSCE 2021 included a simulated patient’s relative requesting a second opinion. The patient was a 62-year-old male with advanced lung adenocarcinoma (Mts in lymph nodes, bone and liver) PDL1 3%. All other markers (EGFR, ALK, ROS1 and Her2) were negative. The tumor progressed at first line with standard chemoimmunotherapy (Carboplatin + Pemetrexed + Pembrolizumab). At the time of consultation, the patient had PS2, depression, hepatic progression without evidence of CNS lesions and all laboratory results were normal. Docetaxel had been recommended as a second line of treatment. The case was sent to each Fellow before the examination, and the evaluation consisted of ten standardized prognostic and therapeutic questions. Results: A total of 16 Oncology Fellows were evaluated. Sex Female/Male (11/5) Age: Mean 33 years (r= 30-35). We analyzed the answers to ten standardized questions (Table). Conclusions: A) The Oncology Fellows agreed on only two out of ten answers to the standardized questions (incurability and mental health referral); and in the remaining eight, disagreement is evident. B) Within the first seven questions, all Fellows differed among themselves in at least one answer. C) These findings coincide with our daily practice: It is highly likely that if a patient gets a second opinion, they will get divergent and even contradictory answers about their case. D) Are these findings a product of differing knowledge or physicians’ noises and biases? Further research could address how medical education and professional development can help with reflecting upon these issues.[Table: see text]
DIPG-15. Major tumor regressions in H3K27M-mutated diffuse midline glioma (DMG) following sequential intravenous (IV) and intracerebroventricular (ICV) delivery of GD2-CAR T-cells
Authors: Michelle Monje, Robbie Majzner, Jasia Mahdi, Sneha Ramakrishna, Shabnum Patel, Harshini Chinnasamy, Kristen Yeom, Liora Schultz, Valentin Barsan, Rebecca Richards, Cynthia Campen, Agnes Reschke, Angus Martin Toland, Christina Baggott, Sharon Mavroukakis, Emily Egeler, Jennifer Moon, Ashley Jacobs, Karen Yamabe-Kwong, Lindsey Rasmussen, Esther Nie, Sean Green, Michael Kunicki, Michele Fujimoto, Zach Ehlinger, Warren Reynolds, Snehit Prabhu, Katherine E Warren, Tim Cornell, Sonia Partap, Paul Fisher, Gerald Grant, Hannes Vogel, Bita Sahaf, Kara Davis, Steven Feldman, Crystal Mackall
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: H3K27M-mutated DMGs express high levels of the disialoganglioside GD2 and GD2-CAR T-cells (GD2-CART) regress DMG in preclinical models. METHODS: NCT04196413 is a 3 + 3 Phase I dose escalation trial testing GD2-CART in patients with biopsy-proved H3K27M DMG, with dose-limiting toxicities (DLT) considered independently for DIPG and spinal DMG (sDMG). Arm A tested escalating doses of IV GD2-CART (DL1=1e6 GD2-CART/kg; DL2=3e6 GD2-CART/kg) following lymphodepletion (LD). After the DLT period, patients with clinical and/or radiographic benefit were eligible for subsequent ICV GD2-CART infusions (10-30e6 GD2-CART) administered via Ommaya without LD. RESULTS: Twelve subjects were treated after standard radiotherapy, 7 of whom began treatment at the time of progression [n=4 DL1 (3 DIPG/1 sDMG); n=8 DL2 (6 DIPG/2 sDMG)]. No DLTs were observed on DL1. Three subjects experienced DLT on DL2 (2 DIPG/1 sDMG) due to grade-4 cytokine release syndrome (CRS). On both dose levels, all subjects exhibited transient symptoms related to on-tumor inflammation, termed Tumor Inflammation-Associated Neurotoxicity (TIAN); no DLT due to TIAN has occurred. Ten subjects experienced radiographic and/or clinical benefit after IV infusion and received subsequent ICV infusions (median=4 ICV infusions/pt, range=1-7). ICV infusions were not associated with high-grade CRS. Four patients continue to receive ICV infusions on study and have experienced continued clinical and radiographic benefit, currently 7-11 months following enrollment. Two patients (one sDMG, one DIPG) have experienced near-complete (&amp;gt;95%) tumor volume reduction. CONCLUSIONS: IV treatment of DIPG and sDMG with GD2-CART is safe at a dose of 1e6/kg, but associated with frequent high-grade CRS at 3e6/kg. ICV GD2-CART has been well tolerated and has mediated impressive sustained clinical benefit in some patients with DIPG/sDMG. Given these findings, we are launching a new arm to assess safety and activity and to define the recommended phase 2 dose for ICV delivery of GD2-CART without LD.
MEDB-88. BAF60C/SMARCD3-mediated novel neurodevelopmental epigenomic program promotes metastatic dissemination in medulloblastoma
Authors: Han Zou, Bradley Poore, Emily Brown, Zhongliang Hu, Xuejun Li, Ian Pollack, Robert Friedlander, Sarah Hainer, Michael Taylor, Baoli Hu
Journal: Neuro-Oncology (2022)

Abstract Normal brain development relies on precise genetic and epigenetic spatiotemporal regulation of gene expression. How dysregulation of neurodevelopment relates to medulloblastoma, the most common pediatric brain tumor, remains elusive. Here, we uncovered a novel neurodevelopmental epigenomic program that regulates Purkinje cell migration in developing cerebellum is hijacked to induce tumor metastatic dissemination in medulloblastoma. Integrating publicly available datasets with our in-house data, unsupervised analyses revealed that BAF60C/SMARCD3, a subunit of SWI/SNF chromatin remodeling complex, promotes tumor cell migration in vitro and metastasis in vivo. Based on analyzing the single-cell RNAseq data of cerebellum developmental trajectory in mice and humans, aligning with the medulloblastoma patients’ datasets, we found that BAF60C/SMARCD3 regulated DAB1-mediated Reelin signaling is involved in Purkinje cell positioning during cerebellum development and medulloblastoma metastasis by orchestrating the cis-regulatory elements (CREs) at the DAB1 gene locus. Analysis of spatiotemporal gene expression and chromatin architecture in the human and mouse cerebellum demonstrated that transcription activity of the BAF60C/SMARCD3-DAB1 circuit is downregulated in a mature state of cerebellar development, however, is upregulated in metastatic medulloblastoma. We further identified that a core set of transcription factors, enhancer of zeste homolog 2 (EZH2) and nuclear factor I X (NFIX), bi-directionally control BAF60C/SMARCD3 transcriptional regulation by coordinating with the CREs at the BAF60C/SMARCD3 gene locus to form a chromatin hub during developing cerebellar development and medulloblastoma metastatic dissemination. Highly expressed BAF60C/SMARCD3 activates the Reelin/DAB1 signaling pathway downstream Src kinase, which was validated in the pair-wised primary and metastatic tumors from medulloblastoma patients. Preclinical medulloblastoma mouse models revealed that inhibiting Src activity reduces tumor cell migration and metastatic dissemination at a lower and safe dose. Together, these data deepen our understanding of how the developmental program influences disease progression and provide an opportunity for the development of therapeutics for this devastating brain cancer in children.
EPCT-04. Stereotactic biopsy split-course radiation therapy for diffuse midline glioma of the pons (SPORT-DMG): Early phase II enrolling clinical trial
Authors: Danielle Cunningham, Jonathan Schwartz, Julie Guerin, Derek Johnson, Soumen Khatua, Nadia Laack, Safia Ahmed, Victoria Michelle Silvera, Debra Brinkmann, Deanna Pafundi, Gesina Keating, Aditya Raghunathan, Caterina Giannini, David Daniels, Anita Mahajan
Journal: Neuro-Oncology (2022)

Abstract Diffuse midline glioma (DMG) of the pons remains the leading cause of death among pediatric patients with brain tumors, despite numerous attempts to intensify treatment. While standard treatment includes 54Gy in 30 fractions of radiation over six weeks of time, nearly all patients progress within the treatment field, and many experience symptomatic radionecrosis with steroid dependence. Symptom improvement typically begins after 20Gy to the tumor. Both hypofractionation and reirradiation after recurrence have been found to be safe for patients with DMG. Our study aims to enroll patients with newly diagnosed pontine DMG aged &amp;gt;1 year (no maximum age), and collect molecular information about DMG via stereotactic biopsy, followed by a short 2 week course of 25Gy in 10 fractions of radiation, with volumes guided by MRI with tractography reconstruction and FDOPA PET radiotracer uptake. Patients are followed closely and can complete the 25Gy in 10 fraction radiation course up to 3 times total for meeting radiographic and clinical progression criteria. Our primary endpoint is to estimate the time to progression from diagnosis to after receiving the second 25Gy course, and to compare this to the historical 7 month standard from diagnosis to progression after one 54Gy course. We aim to improve the time interval where patients are asymptomatic at home while minimizing time receiving daily treatments. Other endpoints will include the patient quality of life, caregiver quality of life, PFS intervals after each course, overall survival, and toxicity.
Detection of targetable fusion alterations in gastric cancer in the Chinese population.
Authors: Zhenhua Liu, Bowen Zhu
Journal: Journal of Clinical Oncology (2022)

e16061 Background: Despite a decreasing incidence and mortality globally, gastric cancer (GC) remains a main threat to public health, especially in China. Consistently, drug therapy is a big challenge for gastric cancer. Although HER2-directed therapy and immune checkpoint inhibitors have achieved great success, other valid targeted drugs are required to develop. Targeted drugs of NTRK gene fusion have been approved in solid tumors including GC by FDA. Moreover, FDA has granted Zenocutuzumab fast-track approval for patients with NRG1 gene fusion in solid tumors. However, in China, gene fusion and functional characterization have not been reported to date in detail. Methods: In order to estimate the fraction of patients who may benefit from targeted drugs, we retrospectively analyzed the fusion alterations in gastric cancer tissue samples from 955 Chinese patients. Remarkably, as fusion partners, all genes included fusion analysis possess experimental or approved drugs. The clinicopathological characteristics were retrieved from the medical records in hospital. Chi-square analysis was used to investigate the relationship of gene fusions with drivers mutations, MSI, TMB and MMR. Results: We found 2.82% (27/955) of patients harboring fusion genes, including MET, ROS1, ALK, FGFR1/2, NTRK, BRAF, EGFR and so on. Among them, EML4-ALK, EWSR1-FLI1 and EGFR-SEPTIN14 have been described in other studies, but 88.9% (24/27) fusion genes are previously unreported. Sequencing results indicate that fusion genes are significantly enriched in patients with ERBB2 gene amplification. In addition, there is no obvious correlation between the positive rate of gene fusion and clinical features including age and gender. Similarly, MSI status, TMB and MMR are included for correlation analysis with gene fusion. Unfortunately, the results are not statistically significant. Conclusions: Our work characterizes the landscape of targetable fusion alterations in gastric cancer in the Chinese population and investigates that targetable fusion testing should be advised to patients with disease progression after receiving standard therapy.
Early clinical safety and pharmacokinetics data of DZD1516, an BBB-penetrant selective HER2 inhibitor for the treatment of HER2-positive metastatic breast cancer.
Authors: Xichun Hu, Jian Zhang, Nicholas Patrick McAndrew
Journal: Journal of Clinical Oncology (2022)

1038 Background: Patients with HER2+ metastatic breast cancer (MBC) are at high risk of developing central nervous system metastases. DZD1516 is a reversible HER2-specific tyrosine kinase inhibitor (TKI) with full blood-brain barrier (BBB) penetration. Here we report the preliminary safety and PK data from the ongoing phase 1 study (NCT04509596) in patients with HER2+ MBC who relapsed from multiple prior treatments. Methods: Eligible patients received single oral dosing of DZD1516 on C0D1 and then twice daily (BID) oral dosing from C1D1 in a continuous 21-day cycle until disease progression, unacceptable toxicity or withdrawal of consent. The primary objective is to investigate the safety and PK of DZD1516 as a single agent. Results: As of 17 January 2022, DZD1516 was explored in 21 HER2+ MBC patients from the USA and China. DZD1516 was well tolerated at doses &lt; 300 mg, BID. Two DLT events were reported in the 300 mg cohort. In all cohorts, 20 (95.2%) patients reported treatment-emergent adverse events (TEAEs), and 3 (14.3%) patients reported grade 3 drug-related TEAE. Two patients had dose interruption and one patient had dose reduction due to TEAE, all in the 300 mg cohort. Majority of TEAEs were reversible. The longest treatment duration was &gt; 3 months. In all cohorts, the most common (&gt; 20%) TEAEs included headache (42.9%), vomiting (38.1%), nausea (23.8%) and hemoglobin decreased (23.8%). At doses &lt; 300 mg, there is no diarrhea or rash reported. PK data showed that combined exposure of DZD1516 and its active metabolite DZ2678 increased in a dose-proportional manner across the dose ranges. Elimination half-life was about 15-19 hrs. About 2-fold accumulation of DZD1516 in AUC was observed on multiple doses. In vitro, both DZD1516 and DZ2678 showed good permeability, and were not substrates of P-gp and BCRP. In patients, K puu,CSF of DZD1516 and DZ2678 was around 2.13 and 0.66, respectively, suggesting good CNS penetration. At the time of data cutoff, 16 patients had at least one post treatment anti-tumor assessment. With a median of 7 lines of prior treatment, the best anti-tumor response was stable disease. Conclusions: Preliminary clinical data showed that DZD1516 is a full BBB-penetrant HER2 TKI, with good safety profile. Consistent with its high selectivity, no wide type EGFR related AEs have been reported. Further evaluation of its safety and efficacy is ongoing. Clinical trial information: NCT04509596. [Table: see text]
OASIS pivotal trial to evaluate the safety and efficacy of the RENOVA iStim System™ for the treatment of women with overactive bladder
Authors: F.M.J. Martens, S. De Wachter, J. Van Breda, L.P.W. Witte, T. Brits, M.A.C. Smits, O. Padron, S. Sutherland, P. Toozs-Hobson, A.G. Digesu, K.J. Cline, R. Dmochowski, J.P.F.A. Heesakkers
Journal: European Urology (2022)
RARE-01. Cerebral infarction in childhood-onset craniopharyngioma patients: results of KRANIOPHARYNGEOM 2007
Authors: Svenja Boekhoff, Brigitte Bison, Maria Eveslage, Carsten Friedrich, Jörg Flitsch, Hermann L Müller
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: Cerebral infarction (CI) is a known vascular complication following treatment of suprasellar tumors. Risk factors for CI, incidence rate, and long-term prognosis are unknown for patients with childhood-onset craniopharyngioma (CP). METHODS: MRI of 244 CP patients, recruited between 2007 and 2019 in KRANIOPHA-RYNGEOM 2007, were reviewed for CI. Risk factors for CI and outcome after CI were analyzed. RESULTS: Twenty-eight of 244 patients (11%) presented with CI based on reference assessment of MRI. One CI occurred before initial surgery and one case of CI occurred after release of intracystic pressure by a cyst catheter. 26 of 28 CI were detected after surgical tumor resection at a median postoperative interval of one day (range: 0.5 - 53 days). Vascular lesions during surgical procedures were documented in 7 cases with CI. No relevant differences with regard to surgical approaches were found. In all 12 irradiated patients, CI occurred before irradiation. Multivariable analyses showed that hydrocephalus and gross-total resection at the time of primary diagnosis / surgery both were risk factors for CI. After CI, quality of life (PEDQOL) and functional capacity (FMH) were impaired. CONCLUSIONS: CI occurs in 11% of surgically-treated CP cases. Degree of resection and increased intracranial pressure are risk factors, which should be considered in the planning of surgical procedures for prevention of CI.
Real-world experience on the efficacy and tolerability of biweekly trifluridine/tipiracil with or without bevacizumab in metastatic colorectal cancer.
Authors: Choon Seong Ang, Qin Jian Low, Carol LF Ho, Robert John Walsh, Yugarajah Asokumaran, Joan RE Choo, Gloria HJ Chan, Jingshan Ho, Yvonne Ang, Hon Lyn Tan, Wei-Peng Yong, Raghav Sundar, Cheng Ean Chee
Journal: Journal of Clinical Oncology (2022)

3584 Background: Trifluridine/tipiracil (TAS-102) is currently approved as third-line treatment in metastatic colorectal cancer (mCRC). However, there is paucity of real-world data on the tolerability and efficacy with biweekly dosing as monotherapy or in combination with bevacizumab. In this study, we present our center’s experience with biweekly TAS-102 with or without bevacizumab in mCRC patients (pts). Methods: We performed a single center retrospective observational study of pts receiving TAS-102 between 2018 and 2021. Results: A total of 83 pts were included (53 men, 30 women), with a median age of 64 years. Majority of pts were treated with TAS-102 in the 3rd-line (48.2%) and 4th-line (28.9%) setting. Almost all (94.0%) were of ECOG ≤ 1 at the initiation of treatment. The mean number of cycles administered was 3.8 and bevacizumab (5mg/kg on Day 1, every 2 weeks) was used in combination with TAS-102 in 18 pts (21.7%). Majority of pts (84.3%) were given TAS-102 using the biweekly regimen (35mg/m2 BD, on Day 1-5 and 15-19, q28 days) rather than standard regimen (35mg/m2 BD, on Day 1-5 and 8-12, q28 days) following a change in institutional practice. Fifteen pts (18.1%) had their initial dose reduced to 30mg/m2 BD at prescriber's discretion. Median PFS and OS were 2.37 and 10.15 months, respectively. In terms of tolerability, fatigue (any grade, 42.2%) and neutropenia (any grade, 44.6%) were the two most common adverse events reported. Grade 3 or higher neutropenia and febrile neutropenia were 16.9% and 3.6%, respectively. Dose reduction during treatment was required in 15 pts (18.1%), dose delay in 31 pts (37.3%) and six pts (7.2%) discontinued treatment due to toxicity. More than half (54.2%) had at least an additional line of therapy (regorafenib, clinical trials or re-challenge previous chemotherapy agents) following disease progression with TAS-102. Conclusions: We report the largest real-world experience with biweekly TAS-102. Our pts treated with TAS-102 had comparable median PFS to the RECOURSE cohort but with significantly better OS as more than half continued to receive treatment. Biweekly dosing of TAS-102 with or without bevacizumab is well tolerated with significantly lower rates of Grade 3 neutropenia compared to the published data in the literature.